In both vertebrates and invertebrates, serotonin (5HT) signaling regulates a vast array of behavior and physiological processes. The genetic basis and molecular mechanisms underlying the complexity of 5HT phenotypes are not well understood. Thus elucidation of genes and molecular mechanisms that regulate the development and function of 5HT neurons will provide insights into the principles of neuronal diversity and reveal reciprocal effects of the nervous system and physiology at molecular and cellular levels. Taking the advantage of sophisticated C. elegans genetics, our unique mutants, and molecular markers that allow a quantifiable measure of 5HT production at the resolution of single cells in living animals, we are undertaking genetic dissection of the 5HT system, testing a central hypothesis: 5HT production in different neurons is regulated by different transcription factors and is modulated by different mechanisms in response to different internal and external environmental stimuli to subserve different physiological functions. This proposal has four specific objectives. (1) By genetic mapping of our collected mutants and RNA-interference screens, we will define new genes that specify 5HT identity and that regulate 5HT production in identified neurons. (2) Using suppressor genetics, we will follow our discovery that a TRP channel at the sensory ending of a pair of 5HT neurons controls 5HT production by defining components that interact with and that act downstream of the channel. (3) Using molecular, cellular, and behavioral approaches, we will organize so identified genes into molecular and cellular pathways. (4) Using our established paradigms, we will test whether specific signaling cascades in specific 5HT neurons modulate specific behavior and if they control distinct stress responsive pathways. Drugs that target the 5HT system are the most commonly prescribed therapeutics for the treatment of depression and many behavioral and neuropsychiatric disorders. Identification of genes and biochemical pathways that regulate 5HT signaling in a model organism will lead to compelling new candidates to be tested in association studies with the diseases, potentially leading to novel diagnostics and new medications.